Device for extracorporeal treatment of physiological fluids of organism

ABSTRACT

A device for extracorporeal treatment of physiological fluids of organism has means forming a filtration membrane for filtering smaller-size components of a physiological fluid withdrawn from a patient from larger-size components of the same, a bed of particulate adsorbing material with which the smaller-size components are contacted for purification, and means for combining the purified smaller-size components of the fluid with the larger-size components of the fluid for returning the thusly treated fluid to a patient.

BACKGROUND OF THE INVENTION

The present invention relates generally to devices for extracorporealtreatment of physiological fluids of organism, in particular, ahemoperfusion device for blood detoxification.

Dialysis is a commonly used physical treatment that removes excesswater, electrolytes, urea and toxins from a patients physiologicalfluid. It is known to perform dialysis by passing physiological fluidssuch as blood along one side of a dialysis membrane and a specialdialysate liquid along the other side. The known dialysis membranes aregenerally permeable to small molecular weight components of solutionsand these components, by diffusing through the membrane, are exchangedbetween the above two liquids. Toxic metabolites of the physiologicalfluid, after passing the membrane, can thus be removed from the organismby the flow of the dialysate liquid. However, diffusion is a relativelyslow process, so that 3 to 4 hours are needed for a sufficient clearanceof blood. Moreover, the removal of larger toxic components from blood,the so called “middle molecular weight toxins”, is much too slow, ifpossible at all, by the technique, because even the modern highpermeable membranes used for hemodialysis must have a cut-off below40-50 kD. This technique is useless if large toxic compounds are neededto be removed from the physiological fluid, such as endotoxins or tissuedestruction products. In some acute cases of poisoning or drug overdose,the hemodialysis technique can prove to be too slow, as the diffusion oftoxins trough the membrane would require such a long time, that wouldmake the whole treatment impractical. Another disadvantage of thehemodialysis treatment is that it requires a complicated and expensiveequipment and highly skilled medical personal and, therefore, cannot bequickly provided in emergency situations outside an adequate medicalinstitution.

A much faster technique for removing unwanted compounds from aphysiological fluid is the adsorption. It is known to pass the bloodthrough a cartridge with activated carbon or polymeric adsorbent. Such ahemoperfusion treatment can be very efficient for rapid removing of bothsmall and middle molecular weight toxins from blood or plasma. With therecent development of adsorption technologies, extremely efficientselective and non-selective polymeric adsorbing materials becomeavailable. The drawback of this technique is that highly efficientadsorbing materials are generally not hemocompatible. They quickly causea series of adverse reactions of biological systems, complementactivation and, finally, clotting of blood.

In order to enhance the biocompatibility, the adsorbing materials haveto be chemically modified. Usually, polar functional groups orhemocompatible polymeric chains are introduced onto the surface ofpolymer beads, as suggested for example in U.S. Pat. No. 5,773,384 byDavankov et al. (1998). Korshak et al. in U.S. Pat. No. 4,140,652,(1978) suggested binding and cross-linking human serum albumin on thesurface of a polystyrene-type adsorbing material. All these coverings,however, dramatically reduce the rate of mass transfer, slow down theadsorption process, diminish the adsorption capacity of the material ina reasonable period of time available for the patient treatment.Needless to say that any additional chemical treatment of the baseadsorbing material increases its prize.

The above high requirements to the hemocompatibility of the adsorbingmaterials can be reduced significantly if blood cells and especiallyplatelets and white blood cells are prevented from contacting directlythe surface of the adsorbent. In other words, after separating cellularmaterial of blood by some kind of hemofiltration, the remaining plasmacan be quickly detoxificated with an efficient and inexpensive sorbentmaterial.

Several kinds of continuous hemofiltration have been suggested. Gorsuchand Atkin (U.S. Pat. No. 5,151,082, 1992) suggest hollow fiberhemofiltration membranes to be surgically introduced into patientsveins, in order to take plasma, instead of the whole blood, forthesubsequent extracorporeal treatment.

Another procedure and device is also known, as disclosed for example inthe article “The Concept of Sorbents in Hemodialysis”, published in “TheInternational Journal of Artificial Organs” volume 21, no. 6, 1998,pages 303-308. In this procedure a device is proposed which includes ahemofilter, a bioseparator and a hemodialyzer. The hemofilter separatesthe blood, so as to retain the blood cells and allow passage of a liquidcomponent of the blood. The liquid component of the blood is supplied tothe bioseparator which accommodates charcoal or adsorbing resin and ispurified there, and then the purified liquid component together with thecells are supplied into the hemodializer. A similar system consisting ofthree separate units, a hemofiltration cartridge, a plasmaperfusionunit, and a hemodialyser, was earlier described in U.S. Pat. No.5,194,157 (1993) by Ghezzi et al.

A complicated system, that allows a simultaneous combination of dialysisand filtration procedures, is subject of U.S. Pat. No. 5,536,412 (1996)by Abe et al. Here, blood is allowed to flow along one side of amembrane, whereas a suspension of a fine dispersed adsorbing material ina dialysate liquid is pumped, in a pulsation-type flow, along the otherside of the membrane. Because of alternating pressure and vacuum, a veryintense exchange of liquids through the membrane is accomplished.

All these systems are too complicated to be applied in a short period oftime. Besides, they require a very substantial amount of blood to beinvolved into extracorporeal circuits, which is difficult to betolerated by the patient.

An original compact plasma filter—sorbent system was suggested byShettigar et al. (U.S. Pat. No. 5,211,850, 1993). Here, blood is pumpedthrough a hollow fiber membrane-type hemofilter, that is placed into aclosed chamber filled with adsorbing material. Plasma is supposed tofiltrate into the chamber from the initial portion of the fibers,interact with the sorbent in the chamber and be resorbed through thesame membrane in the second part of the fibers. This device minimizesthe amount of blood involved into processing and provides an efficientcontact between the filtrate, i.e., plasma with the polymer sorbent. Aserious disadvantage of such a close device, however, is that it isimpossible to observe the movement of the fluids within the device andregulate the flows. Moreover, it is difficult to distribute theadsorbent between the hollow fibers and impossible to separatelyregenerate and reuse the membrane and the adsorbent material.

SUMMARY OF THE INVENTION

Accordingly, it is an object of present invention to provide devices forextracorporeal treatment of physiological liquids of organism, inparticular blood, which avoid the disadvantages of the prior art.

In keeping with these objects and with others which will become apparenthereinafter, one feature of the present invention resides in a devicewhich has means forming a filtration membrane for filtering smaller-sizecomponents of a physiological fluid withdrawn from a patient fromlarger-size components of the same; a bed of particulate adsorbingmaterial with which the smaller-size components are contacted forpurification; and means for combining the purified smaller-sizecomponents of the fluid with the larger-size components of the fluid forreturning the thusly treated fluid to a patient.

In accordance with a specific embodiment of the invention, the devicehas a housing, means forming a blood inlet for introducing blood intothe housing and means forming a blood outlet for withdrawing blood fromthe housing, means forming a hemofiltration membrane which isaccommodated in the housing downstream of the blood inlet and formed sothat blood cells substantially pass along the hemofiltration membranedirectly to the blood outlet while blood plasma is filtered through thehemofiltration membrane from blood cells and flows into an interior ofthe housing, and a body of particulate adsorbing material accommodatedin the housing and located downstream of the hemofiltration membrane sothat the blood plasma separated from the blood cells by thehemofiltration membrane passes through the body of adsorbing materialwhich removes toxins from the blood plasma, and the blood plasma afterremoval of the toxins flows toward the blood outlet to be mixed with theblood cells to be withdrawn through the blood outlet.

When the device is designed in accordance with the present invention, itremoves substantially small molecular weight and middle molecular weighttoxin molecules from the physiological fluid of organism and no previousseparation of blood is needed into the cell-containing component andliquid-containing component. The separation of the cells from the liquidcomponent was (conventionally) performed in the prior art because if thecells also pass through the charcoal or adsorbing resin material, theywould be damaged.

The novel features which are considered as characteristic for thepresent invention are set forth in particular in the appended claims.The invention itself, however, both as to its construction and itsmethod of operation, together with additional objects and advantagesthereof, will be best understood from the following description ofspecific embodiments when read in connection with the accompanyingdrawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 of the drawings is a view showing a device for purification ofphysiological liquids of organism in accordance with the presentinvention.

DESCRIPTION OF PREFERRED EMBODIMENTS

The device has a preferably cone-shaped housing 1 which serves toincorporate both a hemofiltration membrane 2 and a particulate adsorbingmaterial 7. The housing 1 is provided with an upper cup 5 that serves asa blood inlet and a lower cup 6 that serves as a blood outlet. Bloodinlet and blood outlet chambers are formed downstream of the inlet andupstream of the outlet correspondingly. The two cups and the housingrepresent the outer part of the closed device which is intended to beinstalled into a extracorporeal blood circuit. The device receives theblood from the patient, purifies it from toxic components and returnsthe blood to the patient. A peristaltic pump or any other device providethe purification device with an appropriate flow of the physiologicalfluid, and the purification device can be used in combination with aconventional hemodialysis system or without the latter.

The interior of the purification device accomplishes two differentprocesses. The first process is hemofiltration that separates bloodsells from plasma. One of possible ways of achieving this goal is usinghollow fiber-type membrane with a sufficient permeability. If the poresize of the hemofiltration membrane amounts to 0.1 to 1.0 μm, the bloodcells would remain inside the hollow fiber and would be transporteddirectly from the upper space between the upper cup 5 and the housing 1toward the lower space between the housing 1 and the lower cup 6. Themost preferred pore size of the hollow fiber membrane is 0.4-0.6 μm. Thebundle of the hollow fibers is imbedded into a cylindrical polymericslab 3 that tightly separates the space between the upper cup 5 and theinterior of the housing 1. The opposite end of the hollow fiber bundleis also embedded into a cylindrical polymeric slab 4 of a largerdiameter, that, in contract to the slab 3, has a cylindrical opening inthe middle. The slab 4 is tightly installed between the housing 1 andthe lower cup 6. It, however leaves an access to the interior of thedevice.

The cone-shaped interior of the device is intended to be filled withparticulate absorbing material 7. The latter can be simply introducedinto the free space of the device, or, alternatively, be fits packedinto a perforated thinwall polymeric cartridge 8. The latter can openthe possibility to easily dismantle the device, remove the adsorbingmaterial, regenerate it and reuse in the same manner. In any case, thespace filled with the polymer is closed with another round piece 9 thattightly fits into the opening in the polymeric slab 4, and only leaves acentral round opening 10 that incorporates a mesh with a plurality ofopenings of about 50 to 100 μm. This mesh prevents the adsorbingparticles to exit the zone 7.

The device functions as follows. Due to the pressure applied by theblood pump in the inlet part 5 of the device, blood is forced to passthrough the hollow fibers toward the outlet part 6. Since the walls ofthe fibers are porous, major part of plasma escape from the fibers intothe interior of the cartridge. Only the blood cells that are too big todiffuse through the membrane are forced to move along the fiber channelstoward the outlet end of the device and exit there in a ratherconcentrated form. The plasma that has left the hollow fibers has noother way to go than through the polymer packing 7 and toward the onlyavailable exit 10 in the mes-protected opening in the round piece 9.

There in the space formed by the lower cup 6, plasma is mixed with theblood cells which exit the hollow fiber channels. This lower chamber ofthe device is provided with a folded insert 11 that introducesturbulence into the flow and provides for better mixing of the plasmaand the cells, before they exit the device.

The basic advantage of the device, as compared with conventionalhemoprefusion cartridge, is that platelets and blood cells are separatedfrom the adsorbing material. The latter therefore does not need to beextremely hernocompatible, it is sufficient for it to beplasmacompatible. The sorbing material can thus possess a highly activesurface for an efficient and rapid removing of various toxins from theplasma.

The simple design of the cartridge permits to keep minimal dead zones ofthe device and reduce the total volume of the blood required for fillingcompletely the device to an amount of less than 300 ml, preferably to200 ml. Highly open and active surface of the adsorbing material makesit possible to quickly remove the undesired toxins from the plasma.

Both protein-bonded toxins, and free toxins, including middle-sizetoxins are efficiently removed. The preferred size of particulateadsorbing material used in the cartridge is between 200 and 900 μm, morepreferably, between 300 and 600 μm.

As adsorbing materials useful for the device, many kinds of activatedcarbon, hypercrosslinked polystyrene adsorbing resins, mesoporouspolydivinylbenzene resins, specialty ion exchange resins, as well as anykind of specific affinity sorbents and antibody bearing matrixes can beimplied. For these expensive type materials, the possibility of removingfrom the used cartridge, regeneration and reuse, can be of interest,whereas other nonspecific materials can be used in the form of adisposable cartridge.

The basic idea of the new device, namely combination of thehemofiltration process and plasmaperfusion within one single disposablecartridge, can, naturally be realized with some variations of theconstruction. For instance, the bundle of hollow fiber membranes device“HFD” can have different number of fibers and different lengths.Normally, the inner diameter of the hollow fiber should amount to 150 to300 μm, the length between 10 and 100 cm, the internal surface areabetween 0.1 and 5 sq.m, preferably about 0.5 sq.m. These parameters areselected so as to force about 40 to 70% of the initial blood volume tofiltrate through the fiber walls, in the form of plasma. A preferredamount of the filtrate is 50 to 60%. In the case that the hollow fibers2 are longer that the height of the housing 1, the former should bearranged in the form of a helix along the walls of the housing by asimple rotation of the cylindrical slab 3 with respect to the lower slab4. In another variant, parallel plate dialyzer “PPD” membrane could beinstalled instead of the hollowfiber-type membranes. The only essentialrequirement is that major part of the plasma filtrates from the initialblood through the membrane and then efficiently migrates through the bedof the sorbent material.

The ease of mounting and operating the blood purification device must beof great benefit for emergency situations and treating patients outsidea regular hospital. Because of a small flow resistance, the cartridgecan also be operated without an external pumping system, by justexploiting the pressure difference between an artery and a vein of apatient, which normally can amount to 50 to 100 Hg mm.

Wherein the device is designed in accordance with the present invention,it basically removes small molecular weight and middle molecular weighttoxin molecules from the blood. Depending on the nature of the cartridgepacking, the device can also regulate the electrolyte composition of thephysiological fluid, as well as release some deficient components ordrugs into the liquid. Installing materials with immobilized enzymes,immobilized living cells, or chemically reactive polymers allowsconducting chemical transformations on certain components of plasma.Mixed packings of the device that accomplish two or more differenttasks, are also feasible.

Though the above presented consideration mainly deals with bloodpurification, small changes in the construction of the device or certainchanges in the parameters of its two basic components, i.e., themembrane and adsorbing material, can open new possibilities topurification or adjusting the composition of other, than blood,physiological fluids, e.g., blood plasma. By changing the size of thepores of the hollow fiber membrane, one can influence the cutoffthreshold of the filtration process thus operating in the mode ofhemofiltration or plasmafiltration. Indeed, a series of hemocompatiblehollow fiber membranes is available with different cutoffs. Well knownmembranes are F-80 (50,000 m.w. cutoff, Fresenius USA, inc., WalnutCreek, Calif.), Altrex 140 (70,000 m.w. cutoff, Altin Medical, inc.Miami Lakes, Fla.), Plasmaflow (1,000,000 m.w. cutoff, Asahi MedicalCo., Ltd. Tokyo, Japan) and others.

It will be understood that each of the elements described above, or twoor more together, may also find a useful application in other types ofconstructions differing from the types described above.

While the invention has been illustrated and described as embodied indevice for blood purification, it is not intended to be limited to thedetails shown, since various modifications and structural changes may bemade without departing in any way from the spirit of the presentinvention.

Without further analysis, the foregoing will so fully reveal the gist ofthe present invention that others can, by applying current knowledge,readily adapt it for various applications without omitting featuresthat, from the standpoint of prior art, fairly constitute essentialcharacteristics of the generic or specific aspects of this invention.

What is claimed as new and desired to be protected by letters patent isset forth in the appended claims:

What is claimed is:
 1. A device for extracorporeal treatment ofphysiological fluids of an organism, comprising means forming afiltration membrane for filtering smeller-size components of aphysiological fluid withdrawn from a patient from larger-size componentsof the said physiological fluid, a bed of particulate porous adsorbingmaterial with which the smaller-size components are contacted forpurification: means for combining the purified smaller-size componentsof the fluid with the larger-size components of the fluid for returningthe thusly treated fluid to a patient; an inlet chamber with an inlet; ahousing; and an outlet chamber with an outlet said filtration membraneforming means comprising, a plurality of hollow fibers, said hollowfibers and said bed of particulate material being arranged so that saidhollow fibers transport the larger-size components of said fluiddirectly from the inlet chamber into the outlet chamber, while releasinga filtrate of smaller-size components or the fluid into the interior ofthe housing, and said bed of particulate adsorbing material enablingpassage of said filtrate of smaller-size components in the interior ofthe housing and said filtrate's directly into the outlet chamber withoutpassing again through said hollow fibers, said outlet chamber locatedwherein a flow of the larger-size components is mixed with a flow of thetreated smaller-size components of the physiological fluid before saidphysiological fluid exits the device and returns to the patient.
 2. Adevice as defined in claim 1, wherein said hollow fibers formhemofiltration membranes, the physiological fluid is blood, thelarger-size components of the fluid are blood cells, and thesmaller-size components of said fluid is blood plasma.
 3. A device asdefined in claim 2, wherein said hemofiltration membranes are parallelplate dialyzer membranes.
 4. A device as defined in claim 1, whereinsaid particulate adsorbing material is a material selected from groupconsisting of activated carbon, hypercrosslinked polystyrene sorbents,macroporous and mesoporous divinylbenzene-styrene copolymers, porousacrylic polymers, immobilized enzymes, immune sorbents,hydrogel-immobilized living hepatic cells, ion-exchanging resins andcontrolled drug releasing polymers.
 5. A device as defined in claim 1,wherein said housing has a conical shape with a cross-section increasingfrom said inlet to said outlet.
 6. A device as defined in claim 1,wherein said bed of adsorbing material has a substantially conical shapewhich increases in direction from said inlet toward said outlet and islocated inside said hemofiltration membrane which has a correspondinginner conical shape for receiving said bed of adsorbing material.
 7. Adevice as defined in claim 1, wherein said membrane is composed of saidhollow fibers extending in direction from said inlet to said outlet; andfurther comprising means for retaining said hollow fibers at twolocations spaced from one another in direction from said inlet to saidoutlet.
 8. A device as defined in claim 7, wherein said retaining meansincludes two retaining polymeric disks arranged so that one of saidretaining disks is located adjacent to said inlet and is spaced from thelatter so as to form a blood inlet chamber, while the other of saidretaining disks is located adjacent to said blood outlet and spaced fromthe latter so as to form a blood outlet chamber.
 9. A device as definedin claim 8, wherein said blood outlet chamber is located between saidbed of adsorbing material and said other retaining disk on one hand andsaid blood outlet on the other hand so that the blood cells and theblood plasma from which toxins are removed is mixed in said outletchamber.
 10. A device as defined in claim 8, wherein said otherretaining polymeric disks has a central opening; and further comprisinga holding mesh arranged between said bed of particulate material andsaid outlet for preventing failing of the adsorbent material toward saidblood outlet, said holding mesh being located inside said opening ofsaid other retaining disk and having an opening for passing the bloodplasma from which toxins are removed.
 11. A device as defined in claim1, wherein said blood outlet chamber is provided with means facilitatingintermixing of the blood cells with the blood plasma from which toxinsare removed.
 12. A device as defined in claim 8, wherein saidfacilitating means is formed as an insert located in said blood outletchamber.
 13. A device as defined in claim 1; and further comprising apermeable conical element which separates said membrane from said bed ofadsorbent material and accommodates said bed of adsorbent material sothat said permeable element together with said of adsorbing material canbe easily removed.